Optimization of NK cell-based cancer therapies

In this thesis, we investigated various strategies to optimize the anti-cancer activity of NK cells. In chapter 2 we provide a review of the effects of various anti-cancer therapies on NK cell function and how NK cells may contribute to the efficacy of these therapies. In chapter 3 we analyzed the effects of an evidence-based moderate-high intensity resistance and aerobic exercise intervention on the function of NK cells from patients with resectable breast or colon cancer. As in murine models, physical exercise was shown to increase NK cell anti-tumor activity. In chapter 4 we report on how a novel bispecific VHH targeting CD16 on NK cells and the epidermal growth factor receptor (EGFR) on tumor cells can enhance the function of both allogeneic peripheral blood NK cells and CD16+ NK92 cells against EGFR-expressing tumor cells. As mentioned, NK cells have the ability to crosstalk with DC. With the development of alternative allogeneic NK cell sources, we explored whether these allogeneic NK cell products have similar potential for DC crosstalk. In chapter 5 we investigated the ability of an allogeneic NK cell product derived from umbilical cord CD34+ hematopoietic progenitor cells, i.e. inaleucel, to activate human MoDC in vitro. Subsequently, we studied its effects on intratumoral DC and the TME. To do so, we developed a gating strategy for cDC in human tumors, which we describe in chapter 6, and in chapter 7 we then report on the analysis of the effect of this NK cell product on single-cell suspensions derived from patients with either primary or metastatic colorectal cancer. We conclude the thesis with a summarizing discussion in chapter 8 where we give an overview of the findings presented in this thesis in the context of ongoing developments in the NK-based cancer immunotherapy field and highlight future direction